EP0686047B1 - Ligands de 5-ht 1a - Google Patents

Ligands de 5-ht 1a Download PDF

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Publication number
EP0686047B1
EP0686047B1 EP94906348A EP94906348A EP0686047B1 EP 0686047 B1 EP0686047 B1 EP 0686047B1 EP 94906348 A EP94906348 A EP 94906348A EP 94906348 A EP94906348 A EP 94906348A EP 0686047 B1 EP0686047 B1 EP 0686047B1
Authority
EP
European Patent Office
Prior art keywords
procedure
selective
compound
radiolabelled
antagonist
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP94906348A
Other languages
German (de)
English (en)
Other versions
EP0686047A1 (fr
Inventor
Ian Anthony Wyeth Laboratories Cliffe
Allan Wyeth Laboratories Fletcher
Alan Chapman Wyeth Laboratories White
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
John Wyeth and Brother Ltd
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John Wyeth and Brother Ltd
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Publication date
Application filed by John Wyeth and Brother Ltd filed Critical John Wyeth and Brother Ltd
Publication of EP0686047A1 publication Critical patent/EP0686047A1/fr
Application granted granted Critical
Publication of EP0686047B1 publication Critical patent/EP0686047B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention relates to certain 5-HT 1A ligands which are radiolabelled with 11 C.
  • 5-HT 1A ligands having specified characteristics can be labelled with with 11 C to give radiolabelled ligands making them particularly useful in, for example, pharmacological screening procedures or in positron emission tomography (PET) studies.
  • the 5-HT 1A ligands that are suitable for such radiolabelling are selective 5-HT 1A antagonists.
  • selective 5-HT 1A antagonists are meant compounds which:
  • the compounds are tested for the 5-HT 1A binding properties by measuring their ability to displace [ 3 H]-8-OH-DPAT from the 5-HT 1A receptor in rat hippocampal membranes according to the procedure of B.S. Alexander and M.D. Wood, J. Pharm. Pharmacol., 1988 40 , 888-891.
  • a compound is regarded as highly potent in this procedure if it has an IC 50 of 50nM or less.
  • the affinity of the compounds for D 2 receptor sites is determined by the procedure of P. Seeman et al., J. Neurochem., 1984, 43 , 221-235.
  • the affinity of the compound for ⁇ 1 sites is determined by the procedure of A.L. Morrow et al., Mol. Pharmacol., 1986, 29 , 321.
  • the affinity of the compound for 5-HT 2A sites is determined by the procedure of R.A. Lyon et al., Mol. Pharmacol., 1987, 31 , 194-199. (The 5-HT 2A site was previously known as the 5-HT 2 site).
  • a compound is regarded as being 25 fold selective if the IC 50 value for each of the D 2 , ⁇ 1 and 5-HT 2A sites as determined above is at least 25 times the IC 50 value for the 5-HT 1A site as determined in Procedure (A).
  • the compound should be 50 fold selective.
  • the compound is 25 fold selective (preferably 50 fold selective) over one or more of the 5-NT 1B , 5-HT 2C , 5-HT 1D , 5-HT 3 , ⁇ 2 , ⁇ and D 1 sites.
  • the affinity for these sites is determined by the following procedures.
  • This procedure determines whether a compound that has 5-HT 1A binding activity (as determined by procedure (A) possesses agonist and/or antagonist activity.
  • Brain 5-HT 1A receptors exist as two populations in the brain i.e. postsynaptic 5-HT 1A receptors and presynaptic somatodendritic 5-HT 1A receptors.
  • the presynaptic receptors are particularly sensitive to the agonist properties of 5-HT 1A receptor ligands and are activated by compounds designated 'partial agonists', which function as antagonists at the postsynaptic receptor.
  • the present invention provides a selective 5-HT 1A -antagonist radio labelled with 11 C.
  • the suitable 5-HT 1A -antagonists which may be radiolabelled are described, for example, in GB-A-2255337.
  • the suitable compounds are
  • the compound has an IC 50 value of 2.2nM according to procedure (A).
  • procedure (B) the percentage inhibition of binding by the compound at 10 -6 M was ⁇ 50% at the following sites:- 5-HT 1B , 5-HT 2C , 5-HT 1D , 5-HT 2A , ⁇ 2 , ⁇ , D 1 , and D 2 (an inhibition of ⁇ 50% at 10 -6 M means that the binding affinity is very low). Its binding affinity at ⁇ 1 , sites was 230 nM.
  • Selective 5-HT 1A antagonists radiolabelled with 11 C are useful as radioligands in Positron Emission Tomography (PET) studies. Such studies are carried out in vivo in animals and more preferably in humans.
  • the 11 C serves as a positron source producing gamma rays. These rays are detected by the PET scanner and the resulting data is processed by computer so as to give information on the distribution of the radioligand in the living subject.
  • PET Positron Emission Tomography
  • the 11 C radiolabelled selective 5-HT 1A antagonist may be used in the PET studies as for example, a research tool or as a diagnostic aid.
  • the potency and duration of an orally or parenterally administered unlabelled drug, which is a 5-HT 1A ligand can be measured by following the displacement of the 11 C labelled selective 5-HT 1A -antagonist from the brain of humans.
  • PET studies using 11 C radiolabelled selective 5-HT 1A ligands can be used to study the distribution and nature of 5-HT 1A receptor sites as a function of disease states (e.g. Alzheimer's Disease or depression) and hence can be used to diagnose such disease stares.
  • the 11 C radiolabelled selective 5-HT 1A antagonists may be prepared by methods known in the art.
  • a precursor of the antagonist may be reacted with a 11 C containing reagent such that the radioisotope is incorporated into the resulting molecule of the antagonist.
  • a phenol precursor of an antagonist may be alkylated with a radiolabelled alkylating agent, e.g. [ 11 C]methyl iodide to provide the antagonist containing a radiolabelled methoxy substituted phenyl group.
  • the [ 11 C]methyl iodide may be produced via [ 11 C]methanol from cyclotron-produced [ 11 C]carbon dioxide.
  • N-(2-(4-(2-hydroxyphenyl)-1-piperazinyl))ethyl)-N-(2-pyridyl)cyclohexane carboxamide may be alkylated with [ 11 C]-methyliodide to give 11 C labelled N-(2-(1-(4-(2-methoxyphenyl))-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Claims (3)

  1. Antagoniste sélectif de 5-HT1A radiomarqué au 11C dans lequel l'antagoniste sélectif de 5-HT1A est le N-(2-(1-(4-(2-méthoxyphényl)-pipérazinyl))-éthyl)-N-(2-pyridinyl)cyclohexanecarboxamide ou un sel pharmaceutiquement acceptable de celui-ci.
  2. [Méthoxy-11C]N-(2-(1-(4-(2-méthoxyphényl)-pipérazinyl))-éthyl)-N-(2-pyridinyl)cyclohexane-carboxamide ou un sel pharmaceutiquement acceptable de celui-ci.
  3. Procédé d'utilisation d'un radioligand comme outil de recherche dans une étude de tomographie par émission de positrons caractérisé en ce que le radioligand est un composé selon la revendication 1 ou la revendication 2.
EP94906348A 1993-02-26 1994-02-17 Ligands de 5-ht 1a Expired - Lifetime EP0686047B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9303968 1993-02-26
GB939303968A GB9303968D0 (en) 1993-02-26 1993-02-26 5-ht1a ligands
PCT/GB1994/000324 WO1994019026A1 (fr) 1993-02-26 1994-02-17 Ligands de 5-ht¿1a?

Publications (2)

Publication Number Publication Date
EP0686047A1 EP0686047A1 (fr) 1995-12-13
EP0686047B1 true EP0686047B1 (fr) 2000-01-12

Family

ID=10731124

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94906348A Expired - Lifetime EP0686047B1 (fr) 1993-02-26 1994-02-17 Ligands de 5-ht 1a

Country Status (12)

Country Link
US (1) US6056942A (fr)
EP (1) EP0686047B1 (fr)
AT (1) ATE188614T1 (fr)
AU (1) AU6009694A (fr)
DE (1) DE69422611T2 (fr)
DK (1) DK0686047T3 (fr)
ES (1) ES2141819T3 (fr)
GB (1) GB9303968D0 (fr)
GR (1) GR3032479T3 (fr)
MX (1) MX9401415A (fr)
PT (1) PT686047E (fr)
WO (1) WO1994019026A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9413772D0 (en) * 1994-07-08 1994-08-24 Wyeth John & Brother Ltd 5-HT1A ligands
CA2396066A1 (fr) * 2000-01-19 2001-07-26 Akzo Nobel N.V. Association de medicaments pour le traitement de depressions et de troubles s'y rapportant, comprenant de la mirtazapine
DE60139032D1 (de) * 2001-08-09 2009-07-30 Miret Lab Neue konservierungssysteme und deren verwendung in kosmetischen mitteln
BRPI0114147B1 (pt) 2001-08-09 2017-06-27 Laboratorios Miret, S.A. Cosmetic or dermatological composition in the form of an emulsion understanding cationic surfaces
DK1437946T3 (da) 2001-10-25 2012-07-23 Miret Lab Anvendelse af et kationisk konserveringsmiddel i fødevareprodukter
PT1470234E (pt) 2002-02-01 2008-11-10 Miret Lab Síntese enzimática de ésteres de n (alfa)-acil-l-arginina
ES2292757T3 (es) 2002-05-08 2008-03-16 Laboratorios Miret, S.A. Nuevos conservantes y sistemas protectores.
JP4730760B2 (ja) * 2004-05-25 2011-07-20 住友重機械工業株式会社 Ｒｉ標識化合物合成システム
US7731940B2 (en) 2006-01-25 2010-06-08 The Regents Of The University Of California Compositions and methods related to serotonin 5-HT1A receptors
US20130064770A1 (en) 2010-05-28 2013-03-14 Ge Healthcare Limited Radiolabeled compounds and methods thereof
GB201112987D0 (en) 2011-07-28 2011-09-14 Ge Healthcare Ltd Novel compound
GB201116359D0 (en) * 2011-09-22 2011-11-02 Ge Healthcare Ltd Novel synthesis method

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0395313A2 (fr) * 1989-04-22 1990-10-31 American Home Products Corporation Dérivés de pipérazine avec une fonction alkyle tertiaire
EP0481744A1 (fr) * 1990-10-19 1992-04-22 JOHN WYETH & BROTHER LIMITED Dérivés de pipérazine
EP0512755A2 (fr) * 1991-05-02 1992-11-11 JOHN WYETH & BROTHER LIMITED Dérivés de pipérazine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR0173310B1 (ko) * 1989-04-22 1999-02-01 폴 에이 리쳐 피페라진 유도체
US4994258A (en) * 1990-03-05 1991-02-19 Merck & Co., Inc. Gamma emitting, CCK-A antagonists for pancreatic imaging

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0395313A2 (fr) * 1989-04-22 1990-10-31 American Home Products Corporation Dérivés de pipérazine avec une fonction alkyle tertiaire
EP0481744A1 (fr) * 1990-10-19 1992-04-22 JOHN WYETH & BROTHER LIMITED Dérivés de pipérazine
EP0512755A2 (fr) * 1991-05-02 1992-11-11 JOHN WYETH & BROTHER LIMITED Dérivés de pipérazine

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CROUZEL ET AL., NUCL.MED.BIOL., vol. 19, no. 8, pages 857 - 870 *
MATHIS ET AL., LIFE SCIENCES, vol. 55, no. 20, pages 403 - 407 *
PIKE ET AL, MED. CHEM. RES., vol. 5, pages 208 - 227 *
PIKE, J.PSYCHOPHARM., vol. 7, no. 2, pages 139 - 158 *

Also Published As

Publication number Publication date
ATE188614T1 (de) 2000-01-15
DK0686047T3 (da) 2000-04-25
DE69422611T2 (de) 2008-10-09
PT686047E (pt) 2000-06-30
GR3032479T3 (en) 2000-05-31
ES2141819T3 (es) 2000-04-01
AU6009694A (en) 1994-09-14
WO1994019026A1 (fr) 1994-09-01
GB9303968D0 (en) 1993-04-14
DE69422611D1 (de) 2000-02-17
EP0686047A1 (fr) 1995-12-13
US6056942A (en) 2000-05-02
MX9401415A (es) 1994-08-31

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